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1. NPM1-mutated myeloid neoplasm with low percentage of blasts

Author

Falini, B., Chiusolo, Patrizia, Fianchi, Luana, Pagano, Livio, Chiusolo P. (ORCID:0000-0002-1355-1587), Fianchi L., Pagano L. (ORCID:0000-0001-8287-928X), Falini, B., Chiusolo, Patrizia, Fianchi, Luana, Pagano, Livio, Chiusolo P. (ORCID:0000-0002-1355-1587), Fianchi L., and Pagano L. (ORCID:0000-0001-8287-928X)

Abstract

n/a

Published
2024

2. DUAL TARGETING OF HODGKIN’S LYMPHOMA BY ANTI-CD30 CAR-T CELLS CO-TRANSDUCED WITH AN ANTI-PDL1 COSTIMULATORY RECEPTOR TO OVERCOME THE IMMUNOSUPPRESSIVE MICROENVIRONMENT

Author

Perriello, V, Martarelli, N, Gentili, M, Capurro, M, Marra, A, Erol, G, Gobbi, M, Tiacci, E, Falini, B, Perriello V. M., Martarelli N., Gentili M., Capurro M., Marra A., Erol G., Gobbi M., Tiacci E., Falini B., Perriello, V, Martarelli, N, Gentili, M, Capurro, M, Marra, A, Erol, G, Gobbi, M, Tiacci, E, Falini, B, Perriello V. M., Martarelli N., Gentili M., Capurro M., Marra A., Erol G., Gobbi M., Tiacci E., and Falini B.

Published
2023

3. SARS-CoV-2 infection in patients with chronic lymphocytic leukemia: The Italian Hematology Alliance on COVID-19 cohort

Author

Merli, M, Ferrarini, I, Merli, F, Busca, A, Mina, R, Falini, B, Bruna, R, Cairoli, R, Marchetti, M, Romano, A, Cavo, M, Arcaini, L, Trentin, L, Cattaneo, C, Derenzini, E, Fracchiolla, N, Marchesi, F, Scattolin, A, Billio, A, Bocchia, M, Massaia, M, Gambacorti-Passerini, C, Mauro, F, Gentile, M, Mohamed, S, Della Porta, M, Coviello, E, Cilloni, D, Visani, G, Federici, A, Tisi, M, Cudillo, L, Galimberti, S, Gherlinzoni, F, Pagano, L, Guidetti, A, Bertu, L, Corradini, P, Passamonti, F, Visco, C, Merli M., Ferrarini I., Merli F., Busca A., Mina R., Falini B., Bruna R., Cairoli R., Marchetti M., Romano A., Cavo M., Arcaini L., Trentin L., Cattaneo C., Derenzini E., Fracchiolla N. S., Marchesi F., Scattolin A., Billio A., Bocchia M., Massaia M., Gambacorti-Passerini C., Mauro F. R., Gentile M., Mohamed S., Della Porta M. G., Coviello E., Cilloni D., Visani G., Federici A. B., Tisi M. C., Cudillo L., Galimberti S., Gherlinzoni F., Pagano L., Guidetti A., Bertu L., Corradini P., Passamonti F., Visco C., Merli, M, Ferrarini, I, Merli, F, Busca, A, Mina, R, Falini, B, Bruna, R, Cairoli, R, Marchetti, M, Romano, A, Cavo, M, Arcaini, L, Trentin, L, Cattaneo, C, Derenzini, E, Fracchiolla, N, Marchesi, F, Scattolin, A, Billio, A, Bocchia, M, Massaia, M, Gambacorti-Passerini, C, Mauro, F, Gentile, M, Mohamed, S, Della Porta, M, Coviello, E, Cilloni, D, Visani, G, Federici, A, Tisi, M, Cudillo, L, Galimberti, S, Gherlinzoni, F, Pagano, L, Guidetti, A, Bertu, L, Corradini, P, Passamonti, F, Visco, C, Merli M., Ferrarini I., Merli F., Busca A., Mina R., Falini B., Bruna R., Cairoli R., Marchetti M., Romano A., Cavo M., Arcaini L., Trentin L., Cattaneo C., Derenzini E., Fracchiolla N. S., Marchesi F., Scattolin A., Billio A., Bocchia M., Massaia M., Gambacorti-Passerini C., Mauro F. R., Gentile M., Mohamed S., Della Porta M. G., Coviello E., Cilloni D., Visani G., Federici A. B., Tisi M. C., Cudillo L., Galimberti S., Gherlinzoni F., Pagano L., Guidetti A., Bertu L., Corradini P., Passamonti F., and Visco C.

Abstract

COVID-19, the disease caused by SARS-CoV-2, is still afflicting thousands of people across the globe. Few studies on COVID-19 in chronic lymphocytic leukemia (CLL) are available. Here, we analyzed data from the CLL cohort of the Italian Hematology Alliance on COVID-19 (NCT04352556), which included 256 CLL patients enrolled between 25 February 2020 and 1 February 2021. Median age was 70 years (range 38–94) with male preponderance (60.1%). Approximately half of patients (n = 127) had received at least one line of therapy for CLL, including 108 (83.7%) who were on active treatment at the time of COVID-19 or received their last therapy within 12 months. Most patients (230/256, 89.9%) were symptomatic at COVID-19 diagnosis and the majority required hospitalization (n = 176). Overall, after a median follow-up of 42 days (IQR 24–96), case fatality rate was 30.1%, and it was 37.5% and 24.4% in the first (25 February 2020–22 June 2020) and second wave (23 June 2020–1 February 2021), respectively (p = 0.03). At multivariate analysis, male sex (HR 1.82, 95% CI 1.03–3.24, p = 0.04), age over than 70 years (HR 2.23, 95% CI 1.23–4.05, p = 0.01), any treatment for CLL given in the last 12 months (HR 1.72, 95% CI 1.04–2.84, p = 0.04) and COVID-19 severity (severe: HR 5.66, 95% CI 2.62–12.33, p < 0.0001; critical: HR 15.99, 95% CI 6.93–36.90, p < 0.0001) were independently associated with poor survival. In summary, we report a dismal COVID-related outcome in a significant fraction of CLL patients, that can be nicely predicted by clinical parameters.

Published
2023

4. Secondary infections worsen the outcome of COVID-19 in patients with hematological malignancies: A report from the ITA-HEMA-COV

Author

Zappasodi, P, Cattaneo, C, Ferretti, V, Mina, R, Ferreri, A, Merli, F, Oberti, M, Krampera, M, Romano, A, Zerbi, C, Ferrari, J, Cavo, M, Marco Salvini, M, Bertù, L, Fracchiolla, N, Marchesi, F, Massaia, M, Marasco, V, Cairoli, R, Scattolin, A, Vannucchi, A, Gambacorti-Passerini, C, Musto, P, Gherlinzoni, F, Cuneo, A, Pinto, A, Trentin, L, Bocchia, M, Galimberti, Coviello, E, Mc, Morotti, A, Falini, B, Turrin, M, Tafuri, A, Billio, A, Gentile, M, Lemoli, M, 37, Venditti, A, Della Porta, M, Lanza, F, Rigacci, L, Tosi, P, Mohamed, S, Corso, A, Luppi, M, Giuliani, N, Busca, A, Pagano, L, Bruno, R, Grossi, P, Corradini, P, Passamonti, F, Arcaini, L, Zappasodi P, Cattaneo C, Ferretti V, Mina R, Ferreri AJ, Merli F, Oberti M, Krampera M, Romano A, Zerbi C, Ferrari J, Cavo M, Marco Salvini M, Bertù L, Fracchiolla N, Marchesi F, Massaia M, Marasco V, Cairoli R, Scattolin AM, Vannucchi AM, Gambacorti-Passerini C, Musto P, Gherlinzoni F, Cuneo A, Pinto A, Trentin L, Bocchia M, Coviello E, MC, Morotti A, Falini B, Turrin M, Tafuri A, Billio A, Gentile M, Lemoli M, Venditti A, Della Porta M, Lanza F, Rigacci L, Tosi P, Mohamed S, Corso A, Luppi M, Giuliani N, Busca A, Pagano L, Bruno R, Grossi P, Corradini P, Passamonti F, Arcaini L., Zappasodi, P, Cattaneo, C, Ferretti, V, Mina, R, Ferreri, A, Merli, F, Oberti, M, Krampera, M, Romano, A, Zerbi, C, Ferrari, J, Cavo, M, Marco Salvini, M, Bertù, L, Fracchiolla, N, Marchesi, F, Massaia, M, Marasco, V, Cairoli, R, Scattolin, A, Vannucchi, A, Gambacorti-Passerini, C, Musto, P, Gherlinzoni, F, Cuneo, A, Pinto, A, Trentin, L, Bocchia, M, Galimberti, Coviello, E, Mc, Morotti, A, Falini, B, Turrin, M, Tafuri, A, Billio, A, Gentile, M, Lemoli, M, 37, Venditti, A, Della Porta, M, Lanza, F, Rigacci, L, Tosi, P, Mohamed, S, Corso, A, Luppi, M, Giuliani, N, Busca, A, Pagano, L, Bruno, R, Grossi, P, Corradini, P, Passamonti, F, Arcaini, L, Zappasodi P, Cattaneo C, Ferretti V, Mina R, Ferreri AJ, Merli F, Oberti M, Krampera M, Romano A, Zerbi C, Ferrari J, Cavo M, Marco Salvini M, Bertù L, Fracchiolla N, Marchesi F, Massaia M, Marasco V, Cairoli R, Scattolin AM, Vannucchi AM, Gambacorti-Passerini C, Musto P, Gherlinzoni F, Cuneo A, Pinto A, Trentin L, Bocchia M, Coviello E, MC, Morotti A, Falini B, Turrin M, Tafuri A, Billio A, Gentile M, Lemoli M, Venditti A, Della Porta M, Lanza F, Rigacci L, Tosi P, Mohamed S, Corso A, Luppi M, Giuliani N, Busca A, Pagano L, Bruno R, Grossi P, Corradini P, Passamonti F, and Arcaini L.

Abstract

The impact of secondary infections (SI) on COVID-19 outcome in patients with hematological malignancies (HM) is scarcely documented. To evaluate incidence, clinical characteristics, and outcome of SI, we analyzed the microbiologically documented SI in a large multicenter cohort of adult HM patients with COVID-19. Among 1741 HM patients with COVID-19, 134 (7.7%) had 185 SI, with a 1-month cumulative incidence of 5%. Median time between COVID-19 diagnosis and SI was 16 days (IQR: 5–36). Acute myeloid leukemia (AML) and lymphoma/plasma cell neoplasms (PCN) were more frequent diagnoses in SI patients compared to patients without SI (AML: 14.9% vs. 7.1%; lymphoma/PCN 71.7% vs. 65.3%). Patients with SI were older (median age 70 vs. 66 years, p = 0.002), with more comorbidities (median Charlson Comorbidity Index 5 vs. 4, p < 0.001), higher frequency of critical COVID-19 (19.5% vs. 11.5%, p = 0.046), and more frequently not in complete remission (75% vs. 64.7% p = 0.024). Blood and bronchoalveolar lavage were the main sites of isolation for SI. Etiology of infections was bacterial in 80% (n = 148) of cases, mycotic in 9.7% (n = 18) and viral in 10.3% (n = 19); polymicrobial infections were observed in 24 patients (18%). Escherichia coli represented most of Gram-negative isolates (18.9%), while coagulase-negative Staphylococci were the most frequent among Gram-positive (14.2%). The 30-day mortality of patients with SI was higher when compared to patients without SI (69% vs. 15%, p < 0.001). The occurrence of SI worsened COVID-19 outcome in HM patients. Timely diagnosis and adequate management should be considered to improve their prognosis.

Published
2022

5. IL3-zetakine combined with a CD33 costimulatory receptor as a Dual CAR approach for safer and selective targeting of AML

Author

Perriello, V, Rotiroti, M, Pisani, I, Galimberti, S, Alberti, G, Pianigiani, G, Ciaurro, V, Marra, A, Sabino, M, Tini, V, Spinozzi, G, Mezzasoma, F, Morena, F, Martino, S, Salerno, D, Ashby, J, Wingham, B, Serafini, M, Martelli, M, Falini, B, Biondi, A, Tettamanti, S, Perriello, Vincenzo Maria, Rotiroti, Maria Caterina, Pisani, Ilaria, Galimberti, Stefania, Alberti, Gaia, Pianigiani, Giulia, Ciaurro, Valerio, Marra, Andrea, Sabino, Marcella, Tini, Valentina, Spinozzi, Giulio, Mezzasoma, Federica, Morena, Francesco, Martino, Sabata, Salerno, Domenico, Ashby, Julian François, Wingham, Brittany, Serafini, Marta, Martelli, Maria Paola, Falini, Brunangelo, Biondi, Andrea, Tettamanti, Sarah, Perriello, V, Rotiroti, M, Pisani, I, Galimberti, S, Alberti, G, Pianigiani, G, Ciaurro, V, Marra, A, Sabino, M, Tini, V, Spinozzi, G, Mezzasoma, F, Morena, F, Martino, S, Salerno, D, Ashby, J, Wingham, B, Serafini, M, Martelli, M, Falini, B, Biondi, A, Tettamanti, S, Perriello, Vincenzo Maria, Rotiroti, Maria Caterina, Pisani, Ilaria, Galimberti, Stefania, Alberti, Gaia, Pianigiani, Giulia, Ciaurro, Valerio, Marra, Andrea, Sabino, Marcella, Tini, Valentina, Spinozzi, Giulio, Mezzasoma, Federica, Morena, Francesco, Martino, Sabata, Salerno, Domenico, Ashby, Julian François, Wingham, Brittany, Serafini, Marta, Martelli, Maria Paola, Falini, Brunangelo, Biondi, Andrea, and Tettamanti, Sarah

Abstract

Acute myeloid leukemia (AML) still represents an unmet clinical need for adult and pediatric patients. Adoptive cell therapy by chimeric antigen receptor (CAR)-engineered T cells demonstrated a high therapeutic potential, but further development is required to ensure a safe and durable disease remission in AML, especially in elderly patients. To date, translation of CAR T-cell therapy in AML is limited by the absence of an ideal tumor-specific antigen. CD123 and CD33 are the 2 most widely overexpressed leukemic stem cell biomarkers but their shared expression with endothelial and hematopoietic stem and progenitor cells increases the risk of undesired vascular and hematologic toxicities. To counteract this issue, we established a balanced dual-CAR strategy aimed at reducing off-target toxicities while retaining full functionality against AML. Cytokine-induced killer (CIK) cells, coexpressing a first-generation low affinity anti-CD123 interleukin-3–zetakine (IL-3z) and an anti-CD33 as costimulatory receptor without activation signaling domains (CD33.CCR), demonstrated a powerful antitumor efficacy against AML targets without any relevant toxicity on hematopoietic stem and progenitor cells and endothelial cells. The proposed optimized dual-CAR cytokine-induced killer cell strategy could offer the opportunity to unleash the potential of specifically targeting CD123+/CD33+ leukemic cells while minimizing toxicity against healthy cells.

Published
2023

6. LABNET AML: AN EFFICIENT NETWORK THAT CONNECTS HEMATOLOGY CENTERS AND LABORATORIES FOR A HIGH-LEVEL DIAGNOSTIC/PROGNOSTIC WORKUP OF AML

Author

Voso, M, Cucci, R, Messina, M, Santoro, A, Divona, M, Albano, F, Ottaviani, E, Bertorelle, R, Guerrasio, A, Gottardi, E, Izzo, B, Tarantini, G, Scardocci, A, Siragusa, S, Forghieri, F, Cairoli, R, Cambo, B, Vallisa, D, Venditti, A, Ferrara, F, Mannina, D, Cilloni, D, La, S, Piciocchi, A, Falini, B, Pane, F, Saglio, G, Vignetti, M, Amadori, S, Voso MT, Cucci R, Messina M, Santoro A, Divona M, Albano F, Ottaviani E, Bertorelle R, Guerrasio A, Gottardi E, Izzo B, Tarantini G, Scardocci A, Siragusa S, Forghieri F, Cairoli R, Cambo B, Vallisa D, Venditti A, Ferrara F, Mannina D, Cilloni D, La SalaE, Piciocchi A, Falini B, Pane F, Saglio G, Vignetti M, Amadori S, Voso, M, Cucci, R, Messina, M, Santoro, A, Divona, M, Albano, F, Ottaviani, E, Bertorelle, R, Guerrasio, A, Gottardi, E, Izzo, B, Tarantini, G, Scardocci, A, Siragusa, S, Forghieri, F, Cairoli, R, Cambo, B, Vallisa, D, Venditti, A, Ferrara, F, Mannina, D, Cilloni, D, La, S, Piciocchi, A, Falini, B, Pane, F, Saglio, G, Vignetti, M, Amadori, S, Voso MT, Cucci R, Messina M, Santoro A, Divona M, Albano F, Ottaviani E, Bertorelle R, Guerrasio A, Gottardi E, Izzo B, Tarantini G, Scardocci A, Siragusa S, Forghieri F, Cairoli R, Cambo B, Vallisa D, Venditti A, Ferrara F, Mannina D, Cilloni D, La SalaE, Piciocchi A, Falini B, Pane F, Saglio G, Vignetti M, and Amadori S

Published
2021

7. Clinical characteristics and risk factors associated with COVID-19 severity in patients with haematological malignancies in Italy: a retrospective, multicentre, cohort study

Author

Passamonti, F, Cattaneo, C, Arcaini, L, Bruna, R, Cavo, M, Merli, F, Angelucci, E, Krampera, M, Cairoli, R, Della Porta, M, Fracchiolla, N, Ladetto, M, Gambacorti Passerini, C, Salvini, M, Marchetti, M, Lemoli, R, Molteni, A, Busca, A, Cuneo, A, Romano, A, Giuliani, N, Galimberti, S, Corso, A, Morotti, A, Falini, B, Billio, A, Gherlinzoni, F, Visani, G, Tisi, M, Tafuri, A, Tosi, P, Lanza, F, Massaia, M, Turrini, M, Ferrara, F, Gurrieri, C, Vallisa, D, Martelli, M, Derenzini, E, Guarini, A, Conconi, A, Cuccaro, A, Cudillo, L, Russo, D, Ciambelli, F, Scattolin, A, Luppi, M, Selleri, C, Ortu La Barbera, E, Ferrandina, C, Di Renzo, N, Olivieri, A, Bocchia, M, Gentile, M, Marchesi, F, Musto, P, Federici, A, Candoni, A, Venditti, A, Fava, C, Pinto, A, Galieni, P, Rigacci, L, Armiento, D, Pane, F, Oberti, M, Zappasodi, P, Visco, C, Franchi, M, Grossi, P, Bertu, L, Corrao, G, Pagano, L, Corradini, P, Passamonti F., Cattaneo C., Arcaini L., Bruna R., Cavo M., Merli F., Angelucci E., Krampera M., Cairoli R., Della Porta M. G., Fracchiolla N., Ladetto M., Gambacorti Passerini C., Salvini M., Marchetti M., Lemoli R., Molteni A., Busca A., Cuneo A., Romano A., Giuliani N., Galimberti S., Corso A., Morotti A., Falini B., Billio A., Gherlinzoni F., Visani G., Tisi M. C., Tafuri A., Tosi P., Lanza F., Massaia M., Turrini M., Ferrara F., Gurrieri C., Vallisa D., Martelli M., Derenzini E., Guarini A., Conconi A., Cuccaro A., Cudillo L., Russo D., Ciambelli F., Scattolin A. M., Luppi M., Selleri C., Ortu La Barbera E., Ferrandina C., Di Renzo N., Olivieri A., Bocchia M., Gentile M., Marchesi F., Musto P., Federici A. B., Candoni A., Venditti A., Fava C., Pinto A., Galieni P., Rigacci L., Armiento D., Pane F., Oberti M., Zappasodi P., Visco C., Franchi M., Grossi P. A., Bertu L., Corrao G., Pagano L., Corradini P., Passamonti, F, Cattaneo, C, Arcaini, L, Bruna, R, Cavo, M, Merli, F, Angelucci, E, Krampera, M, Cairoli, R, Della Porta, M, Fracchiolla, N, Ladetto, M, Gambacorti Passerini, C, Salvini, M, Marchetti, M, Lemoli, R, Molteni, A, Busca, A, Cuneo, A, Romano, A, Giuliani, N, Galimberti, S, Corso, A, Morotti, A, Falini, B, Billio, A, Gherlinzoni, F, Visani, G, Tisi, M, Tafuri, A, Tosi, P, Lanza, F, Massaia, M, Turrini, M, Ferrara, F, Gurrieri, C, Vallisa, D, Martelli, M, Derenzini, E, Guarini, A, Conconi, A, Cuccaro, A, Cudillo, L, Russo, D, Ciambelli, F, Scattolin, A, Luppi, M, Selleri, C, Ortu La Barbera, E, Ferrandina, C, Di Renzo, N, Olivieri, A, Bocchia, M, Gentile, M, Marchesi, F, Musto, P, Federici, A, Candoni, A, Venditti, A, Fava, C, Pinto, A, Galieni, P, Rigacci, L, Armiento, D, Pane, F, Oberti, M, Zappasodi, P, Visco, C, Franchi, M, Grossi, P, Bertu, L, Corrao, G, Pagano, L, Corradini, P, Passamonti F., Cattaneo C., Arcaini L., Bruna R., Cavo M., Merli F., Angelucci E., Krampera M., Cairoli R., Della Porta M. G., Fracchiolla N., Ladetto M., Gambacorti Passerini C., Salvini M., Marchetti M., Lemoli R., Molteni A., Busca A., Cuneo A., Romano A., Giuliani N., Galimberti S., Corso A., Morotti A., Falini B., Billio A., Gherlinzoni F., Visani G., Tisi M. C., Tafuri A., Tosi P., Lanza F., Massaia M., Turrini M., Ferrara F., Gurrieri C., Vallisa D., Martelli M., Derenzini E., Guarini A., Conconi A., Cuccaro A., Cudillo L., Russo D., Ciambelli F., Scattolin A. M., Luppi M., Selleri C., Ortu La Barbera E., Ferrandina C., Di Renzo N., Olivieri A., Bocchia M., Gentile M., Marchesi F., Musto P., Federici A. B., Candoni A., Venditti A., Fava C., Pinto A., Galieni P., Rigacci L., Armiento D., Pane F., Oberti M., Zappasodi P., Visco C., Franchi M., Grossi P. A., Bertu L., Corrao G., Pagano L., and Corradini P.

Abstract

Background: Several small studies on patients with COVID-19 and haematological malignancies are available showing a high mortality in this population. The Italian Hematology Alliance on COVID-19 aimed to collect data from adult patients with haematological malignancies who required hospitalisation for COVID-19. Methods: This multicentre, retrospective, cohort study included adult patients (aged ≥18 years) with diagnosis of a WHO-defined haematological malignancy admitted to 66 Italian hospitals between Feb 25 and May 18, 2020, with laboratory-confirmed and symptomatic COVID-19. Data cutoff for this analysis was June 22, 2020. The primary outcome was mortality and evaluation of potential predictive parameters of mortality. We calculated standardised mortality ratios between observed death in the study cohort and expected death by applying stratum-specific mortality rates of the Italian population with COVID-19 and an Italian cohort of 31 993 patients with haematological malignancies without COVID-19 (data up to March 1, 2019). Multivariable Cox proportional hazards model was used to identify factors associated with overall survival. This study is registered with ClinicalTrials.gov, NCT04352556, and the prospective part of the study is ongoing. Findings: We enrolled 536 patients with a median follow-up of 20 days (IQR 10–34) at data cutoff, 85 (16%) of whom were managed as outpatients. 440 (98%) of 451 hospitalised patients completed their hospital course (were either discharged alive or died). 198 (37%) of 536 patients died. When compared with the general Italian population with COVID-19, the standardised mortality ratio was 2·04 (95% CI 1·77–2·34) in our whole study cohort and 3·72 (2·86–4·64) in individuals younger than 70 years. When compared with the non-COVID-19 cohort with haematological malignancies, the standardised mortality ratio was 41·3 (38·1–44·9). Older age (hazard ratio 1·03, 95% CI 1·01–1·05); progressive disease status (2·10, 1·41–3·12); diagnosis of

Published
2020

8. Metalloproteinase inhibition reduces AML growth, prevents stem cell loss, and improves chemotherapy effectiveness.

Author

Pirillo, C, Birch, F, Tissot, FS, Anton, SG, Haltalli, M, Tini, V, Kong, I, Piot, C, Partridge, B, Pospori, C, Keeshan, K, Santamaria, S, Hawkins, E, Falini, B, Marra, A, Duarte, D, Lee, CF, Roberts, E, Lo Celso, C, Pirillo, C, Birch, F, Tissot, FS, Anton, SG, Haltalli, M, Tini, V, Kong, I, Piot, C, Partridge, B, Pospori, C, Keeshan, K, Santamaria, S, Hawkins, E, Falini, B, Marra, A, Duarte, D, Lee, CF, Roberts, E, and Lo Celso, C

Abstract

Acute myeloid leukemia (AML) is a blood cancer of the myeloid lineage. Its prognosis remains poor, highlighting the need for new therapeutic and precision medicine approaches. AML symptoms often include cytopenias linked to loss of healthy hematopoietic stem and progenitor cells (HSPCs). The mechanisms behind HSPC decline are complex and still poorly understood. Here, intravital microscopy (IVM) of a well-established experimental model of AML allows direct observation of the interactions between healthy and malignant cells in the bone marrow (BM), suggesting that physical dislodgment of healthy cells by AML through damaged vasculature may play an important role. Multiple matrix metalloproteinases (MMPs), known to remodel extracellular matrix, are expressed by AML cells and the BM microenvironment. We reason MMPs could be involved in cell displacement and vascular leakiness; therefore, we evaluate the therapeutic potential of MMP pharmacological inhibition using the broad-spectrum inhibitor prinomastat. IVM analyses of prinomastat-treated mice reveal reduced vascular permeability and healthy cell clusters in circulation and lower AML infiltration, proliferation, and cell migration. Furthermore, treated mice have increased retention of healthy HSPCs in the BM and increased survival following chemotherapy. Analysis of a human AML transcriptomic database reveals widespread MMP deregulation, and human AML cells show susceptibility to MMP inhibition. Overall, our results suggest that MMP inhibition could be a promising complementary therapy to reduce AML growth and limit HSPC loss and BM vascular damage caused by MLL-AF9 and possibly other AML subtypes.

Published
2022

9. The International Consensus Classification of Mature Lymphoid Neoplasms: a report from the Clinical Advisory Committee

Author

Campo, E, Jaffe, ES, Cook, JR, Quintanilla-Martinez, L, Swerdlow, SH, Anderson, KC, Brousset, P, Cerroni, L, de Leval, L, Dirnhofer, S, Dogan, A, Feldman, AL, Fend, F, Friedberg, JW, Gaulard, P, Ghia, P, Horwitz, SM, King, RL, Salles, G, San-Miguel, J, Seymour, JF, Treon, SP, Vose, JM, Zucca, E, Advani, R, Ansell, S, Au, W-Y, Barrionuevo, C, Bergsagel, L, Chan, WC, Cohen, JI, d'Amore, F, Davies, A, Falini, B, Ghobrial, IM, Goodlad, JR, Gribben, JG, Hsi, ED, Kahl, BS, Kim, W-S, Kumar, S, LaCasce, AS, Laurent, C, Lenz, G, Leonard, JP, Link, MP, Lopez-Guillermo, A, Mateos, MV, Macintyre, E, Melnick, AM, Morschhauser, F, Nakamura, S, Narbaitz, M, Pavlovsky, A, Pileri, SA, Piris, M, Pro, B, Rajkumar, V, Rosen, ST, Sander, B, Sehn, L, Shipp, MA, Smith, SM, Staudt, LM, Thieblemont, C, Tousseyn, T, Wilson, WH, Yoshino, T, Zinzani, P-L, Dreyling, M, Scott, DW, Winter, JN, Zelenetz, A, Campo, E, Jaffe, ES, Cook, JR, Quintanilla-Martinez, L, Swerdlow, SH, Anderson, KC, Brousset, P, Cerroni, L, de Leval, L, Dirnhofer, S, Dogan, A, Feldman, AL, Fend, F, Friedberg, JW, Gaulard, P, Ghia, P, Horwitz, SM, King, RL, Salles, G, San-Miguel, J, Seymour, JF, Treon, SP, Vose, JM, Zucca, E, Advani, R, Ansell, S, Au, W-Y, Barrionuevo, C, Bergsagel, L, Chan, WC, Cohen, JI, d'Amore, F, Davies, A, Falini, B, Ghobrial, IM, Goodlad, JR, Gribben, JG, Hsi, ED, Kahl, BS, Kim, W-S, Kumar, S, LaCasce, AS, Laurent, C, Lenz, G, Leonard, JP, Link, MP, Lopez-Guillermo, A, Mateos, MV, Macintyre, E, Melnick, AM, Morschhauser, F, Nakamura, S, Narbaitz, M, Pavlovsky, A, Pileri, SA, Piris, M, Pro, B, Rajkumar, V, Rosen, ST, Sander, B, Sehn, L, Shipp, MA, Smith, SM, Staudt, LM, Thieblemont, C, Tousseyn, T, Wilson, WH, Yoshino, T, Zinzani, P-L, Dreyling, M, Scott, DW, Winter, JN, and Zelenetz, A

Abstract

Since the publication of the Revised European-American Classification of Lymphoid Neoplasms in 1994, subsequent updates of the classification of lymphoid neoplasms have been generated through iterative international efforts to achieve broad consensus among hematopathologists, geneticists, molecular scientists, and clinicians. Significant progress has recently been made in the characterization of malignancies of the immune system, with many new insights provided by genomic studies. They have led to this proposal. We have followed the same process that was successfully used for the third and fourth editions of the World Health Organization Classification of Hematologic Neoplasms. The definition, recommended studies, and criteria for the diagnosis of many entities have been extensively refined. Some categories considered provisional have now been upgraded to definite entities. Terminology for some diseases has been revised to adapt nomenclature to the current knowledge of their biology, but these modifications have been restricted to well-justified situations. Major findings from recent genomic studies have impacted the conceptual framework and diagnostic criteria for many disease entities. These changes will have an impact on optimal clinical management. The conclusions of this work are summarized in this report as the proposed International Consensus Classification of mature lymphoid, histiocytic, and dendritic cell tumors.

Published
2022

10. Consensus opinion from an international group of experts on measurable residual disease in hairy cell leukemia

Author

Ravandi, F, Kreitman, RJ, Tiacci, E, Andritsos, L, Banerji, V, Barrientos, JC, Bhat, SA, Blachly, JS, Broccoli, A, Call, T, Chihara, D, Dearden, C, Demeter, J, Dietrich, S, Else, M, Epperla, N, Falini, B, Forconi, F, Gladstone, DE, Gozzetti, A, Iyengar, S, Johnston, JB, Jorgensen, J, Juliusson, G, Lauria, F, Lozanski, G, Parikh, SA, Park, JH, Polliack, A, Quest, G, Robak, T, Rogers, KA, Saven, A, Seymour, JF, Tadmor, T, Tallman, MS, Tam, CS, Thompson, PA, Troussard, X, Zent, CS, Zenz, T, Zinzani, PL, Woermann, B, Rai, K, Grever, M, Ravandi, F, Kreitman, RJ, Tiacci, E, Andritsos, L, Banerji, V, Barrientos, JC, Bhat, SA, Blachly, JS, Broccoli, A, Call, T, Chihara, D, Dearden, C, Demeter, J, Dietrich, S, Else, M, Epperla, N, Falini, B, Forconi, F, Gladstone, DE, Gozzetti, A, Iyengar, S, Johnston, JB, Jorgensen, J, Juliusson, G, Lauria, F, Lozanski, G, Parikh, SA, Park, JH, Polliack, A, Quest, G, Robak, T, Rogers, KA, Saven, A, Seymour, JF, Tadmor, T, Tallman, MS, Tam, CS, Thompson, PA, Troussard, X, Zent, CS, Zenz, T, Zinzani, PL, Woermann, B, Rai, K, and Grever, M

Abstract

A significant body of literature has been generated related to the detection of measurable residual disease (MRD) at the time of achieving complete remission (CR) in patients with hairy cell leukemia (HCL). However, due to the indolent nature of the disease as well as reports suggesting long-term survival in patients treated with a single course of a nucleoside analog albeit without evidence of cure, the merits of detection of MRD and attempts to eradicate it have been debated. Studies utilizing novel strategies in the relapse setting have demonstrated the utility of achieving CR with undetectable MRD (uMRD) in prolonging the duration of remission. Several assays including immunohistochemical analysis of bone marrow specimens, multi-parameter flow cytometry and molecular assays to detect the mutant BRAF V600E gene or the consensus primer for the immunoglobulin heavy chain gene (IGH) rearrangement have been utilized with few comparative studies. Here we provide a consensus report on the available data, the potential merits of MRD assessment in the front-line and relapse settings and recommendations on future role of MRD assessment in HCL.

Published
2022

11. Prolonged XPO1 inhibition is essential for optimal antileukemic activity in NPM1-mutated AML

Author

Pianigiani, G., Gagliardi, A., Mezzasoma, F., Rocchio, F., Tini, V., Bigerna, B., Sportoletti, P., Caruso, S., Marra, A., Peruzzi, S., Petito, E., Spinozzi, G., Shacham, S., Landesman, Y., Quintarelli, C., Gresele, P., Locatelli, Franco, Martelli, M. P., Falini, B., Brunetti, L., Locatelli F. (ORCID:0000-0002-7976-3654), Pianigiani, G., Gagliardi, A., Mezzasoma, F., Rocchio, F., Tini, V., Bigerna, B., Sportoletti, P., Caruso, S., Marra, A., Peruzzi, S., Petito, E., Spinozzi, G., Shacham, S., Landesman, Y., Quintarelli, C., Gresele, P., Locatelli, Franco, Martelli, M. P., Falini, B., Brunetti, L., and Locatelli F. (ORCID:0000-0002-7976-3654)

Abstract

NPM1 is the most frequently mutated gene in adults with acute myeloid leukemia (AML). The interaction between mutant NPM1 (NPM1c) and exportin-1 (XPO1) causes aberrant cytoplasmic dislocation of NPM1c and promotes the high expression of homeobox (HOX) genes, which is critical for maintaining the leukemic state of NPM1-mutated cells. Although there is a rationale for using XPO1 inhibitors in NPM1-mutated AML, selinexor administered once or twice per week did not translate into clinical benefit in patients with NPM1 mutations. Here, we show that this dosing strategy results in only a temporary disruption of the XPO1-NPM1c interaction, limiting the efficacy of selinexor. Because the second-generation XPO1 inhibitor eltanexor can be administered more frequently, we tested the antileukemic activity of prolonged XPO1 inhibition in NPM1-mutated AML models. Eltanexor caused irreversible HOX downregulation, induced terminal AML differentiation, and prolonged the survival of leukemic mice. This study provides essential information for the appropriate design of clinical trials with XPO1 inhibitors in NPM1-mutated AML.

Published
2022

12. Secondary infections worsen the outcome of COVID-19 in patients with hematological malignancies: A report from the ITA-HEMA-COV

Author

Zappasodi, P., Cattaneo, C., Valeria Ferretti, V., Mina, R., Jose Maria Ferreri, A., Merli, F., Oberti, M., Krampera, M., Romano, A., Zerbi, C., Ferrari, J., Cavo, M., Salvini, M., Bertu, L., Stefano Fracchiolla, N., Marchesi, F., Massaia, M., Marasco, V., Cairoli, R., Maria Scattolin, A., Maria Vannucchi, A., Gambacorti-Passerini, C., Musto, P., Gherlinzoni, F., Cuneo, A., Pinto, A., Trentin, L., Bocchia, M., Galimberti, S., Coviello, E., Chiara Tisi, M., Morotti, A., Falini, B., Turrini, M., Tafuri, A., Billio, A., Gentile, M., Massimo Lemoli, R., Venditti, A., Giovanni Della Porta, M., Lanza, F., Rigacci, L., Tosi, P., Mohamed, S., Corso, A., Luppi, M., Giuliani, N., Busca, A., Pagano, Livio, Bruno, R., Antonio Grossi, P., Corradini, P., Passamonti, F., Arcaini, L., Pagano L. (ORCID:0000-0001-8287-928X), Zappasodi, P., Cattaneo, C., Valeria Ferretti, V., Mina, R., Jose Maria Ferreri, A., Merli, F., Oberti, M., Krampera, M., Romano, A., Zerbi, C., Ferrari, J., Cavo, M., Salvini, M., Bertu, L., Stefano Fracchiolla, N., Marchesi, F., Massaia, M., Marasco, V., Cairoli, R., Maria Scattolin, A., Maria Vannucchi, A., Gambacorti-Passerini, C., Musto, P., Gherlinzoni, F., Cuneo, A., Pinto, A., Trentin, L., Bocchia, M., Galimberti, S., Coviello, E., Chiara Tisi, M., Morotti, A., Falini, B., Turrini, M., Tafuri, A., Billio, A., Gentile, M., Massimo Lemoli, R., Venditti, A., Giovanni Della Porta, M., Lanza, F., Rigacci, L., Tosi, P., Mohamed, S., Corso, A., Luppi, M., Giuliani, N., Busca, A., Pagano, Livio, Bruno, R., Antonio Grossi, P., Corradini, P., Passamonti, F., Arcaini, L., and Pagano L. (ORCID:0000-0001-8287-928X)

Abstract

The impact of secondary infections (SI) on COVID-19 outcome in patients with hematological malignancies (HM) is scarcely documented. To evaluate incidence, clinical characteristics, and outcome of SI, we analyzed the microbiologically documented SI in a large multicenter cohort of adult HM patients with COVID-19. Among 1741 HM patients with COVID-19, 134 (7.7%) had 185 SI, with a 1-month cumulative incidence of 5%. Median time between COVID-19 diagnosis and SI was 16 days (IQR: 5–36). Acute myeloid leukemia (AML) and lymphoma/plasma cell neoplasms (PCN) were more frequent diagnoses in SI patients compared to patients without SI (AML: 14.9% vs. 7.1%; lymphoma/PCN 71.7% vs. 65.3%). Patients with SI were older (median age 70 vs. 66 years, p = 0.002), with more comorbidities (median Charlson Comorbidity Index 5 vs. 4, p < 0.001), higher frequency of critical COVID-19 (19.5% vs. 11.5%, p = 0.046), and more frequently not in complete remission (75% vs. 64.7% p = 0.024). Blood and bronchoalveolar lavage were the main sites of isolation for SI. Etiology of infections was bacterial in 80% (n = 148) of cases, mycotic in 9.7% (n = 18) and viral in 10.3% (n = 19); polymicrobial infections were observed in 24 patients (18%). Escherichia coli represented most of Gram-negative isolates (18.9%), while coagulase-negative Staphylococci were the most frequent among Gram-positive (14.2%). The 30-day mortality of patients with SI was higher when compared to patients without SI (69% vs. 15%, p < 0.001). The occurrence of SI worsened COVID-19 outcome in HM patients. Timely diagnosis and adequate management should be considered to improve their prognosis.

Published
2022

13. Long-term follow-up of cladribine treatment in hairy cell leukemia: 30-year experience in a multicentric Italian study

Author

Pagano, Livio, Criscuolo, Marianna, Broccoli, A., Piciocchi, A., Varettoni, M., Galli, Eugenio, Anastasia, A., Cantonetti, M., Trentin, L., Kovalchuk, S., Orsucci, L., Frustaci, A., Spolzino, A., Volpetti, S., Annibali, O., Storti, Sergio, Stelitano, C., Marchesi, F., Offidani, M., Casadei, B., Nizzoli, M. E., De Luca, M. L., Fianchi, Luana, Motta, M., Guarnera, L., Simonetti, E., Visentin, A., Vassallo, F., Deodato, M., Sarlo, C., Olivieri, A., Falini, B., Pulsoni, A., Tiacci, E., Zinzani, P. L., Pagano L. (ORCID:0000-0001-8287-928X), Criscuolo M., Galli E., Storti S. (ORCID:0000-0002-4374-3985), Fianchi L., Pagano, Livio, Criscuolo, Marianna, Broccoli, A., Piciocchi, A., Varettoni, M., Galli, Eugenio, Anastasia, A., Cantonetti, M., Trentin, L., Kovalchuk, S., Orsucci, L., Frustaci, A., Spolzino, A., Volpetti, S., Annibali, O., Storti, Sergio, Stelitano, C., Marchesi, F., Offidani, M., Casadei, B., Nizzoli, M. E., De Luca, M. L., Fianchi, Luana, Motta, M., Guarnera, L., Simonetti, E., Visentin, A., Vassallo, F., Deodato, M., Sarlo, C., Olivieri, A., Falini, B., Pulsoni, A., Tiacci, E., Zinzani, P. L., Pagano L. (ORCID:0000-0001-8287-928X), Criscuolo M., Galli E., Storti S. (ORCID:0000-0002-4374-3985), and Fianchi L.

Abstract

Hairy cell leukemia (HCL) is a rare lymphoproliferative disease with an excellent prognosis after treatment with cladribine (2CDA), although relapse may occur during follow-up. The aim of the study is to review the efficacy, safety, long-term remission rate, and overall survival (OS) in those patients who received 2CDA as first-line treatment. We retrospectively reviewed data of HCL patients treated with 2CDA between March 1991 and May 2019 at 18 Italian Hematological centers: 513 patients were evaluable for study purpose. The median age was 54 years (range 24–88) and ECOG was 0 in 84.9% of cases. A total of 330 (64.3%) patients received 2CDA intravenously and 183 (35.7%) subcutaneously. ORR was 91.8%: CR was obtained in 335 patients (65.3%), PR in 96 (18.7%), and hematological response in 40 (7.8%) patients; in 42 (8.2%) no response was observed. Hemoglobin value (p = 0.044), frequency of circulating hairy cells (p = 0.039), recovery of absolute neutrophil count (p = 0.006), and normalization of spleen (p ≤ 0.001) were associated with CR compared to PR in univariable analysis. At a median follow-up of 6.83 years (range 0.04–28.52), the median time to relapse was 12.2 years. A significant difference in duration of response was identified between patients that obtained a CR and PR (19.4 years versus 4.8 years, p < 0.0001). Non-hematological grade 3 or higher early toxicity was reported in 103 (20.1%) patients. Median OS was not reached: 95.3%, 92.4%, and 81.8% of patients were estimated to be alive at 5, 10, and 15 years, respectively. Forty-nine patients died (9.5%), following an infection in 14 cases (2.7%), natural causes in 14 (2.7%), cardiovascular events in 13 (2.5%), a second neoplasm in 6 (1.2%), and progression of HCL in 2 cases (0.4%). Following treatment of HCL with 2CDA, 80% of patients are estimated to be alive 15 years after diagnosis.

Published
2022

14. Hairy cell leukemia and COVID-19 adaptation of treatment guidelines

Author

Grever, M, Andritsos, L, Banerji, V, Barrientos, JC, Bhat, S, Blachly, JS, Call, T, Cross, M, Dearden, C, Demeter, J, Dietrich, S, Falini, B, Forconi, F, Gladstone, DE, Gozzetti, A, Iyengar, S, Johnston, JB, Juliusson, G, Kraut, E, Kreitman, RJ, Lauria, F, Lozanski, G, Parikh, SA, Park, J, Polliack, A, Ravandi, F, Robak, T, Rogers, KA, Saven, A, Seymour, JF, Tadmor, T, Tallman, MS, Tam, CS, Tiacci, E, Troussard, X, Zent, C, Zenz, T, Zinzani, PL, Wormann, B, Grever, M, Andritsos, L, Banerji, V, Barrientos, JC, Bhat, S, Blachly, JS, Call, T, Cross, M, Dearden, C, Demeter, J, Dietrich, S, Falini, B, Forconi, F, Gladstone, DE, Gozzetti, A, Iyengar, S, Johnston, JB, Juliusson, G, Kraut, E, Kreitman, RJ, Lauria, F, Lozanski, G, Parikh, SA, Park, J, Polliack, A, Ravandi, F, Robak, T, Rogers, KA, Saven, A, Seymour, JF, Tadmor, T, Tallman, MS, Tam, CS, Tiacci, E, Troussard, X, Zent, C, Zenz, T, Zinzani, PL, and Wormann, B

Abstract

Standard treatment options in classic HCL (cHCL) result in high response rates and near normal life expectancy. However, the disease itself and the recommended standard treatment are associated with profound and prolonged immunosuppression, increasing susceptibility to infections and the risk for a severe course of COVID-19. The Hairy Cell Leukemia Foundation (HCLF) has recently convened experts and discussed different clinical strategies for the management of these patients. The new recommendations adapt the 2017 consensus for the diagnosis and management with cHCL to the current COVID-19 pandemic. They underline the option of active surveillance in patients with low but stable blood counts, consider the use of targeted and non-immunosuppressive agents as first-line treatment for cHCL, and give recommendations on preventive measures against COVID-19.

Published
2021

15. Clinical significance of chromatin-spliceosome acute myeloid leukemia: a report from the Northern Italy Leukemia Group (NILG) randomized trial 02/06

Author

Caprioli, C, Lussana, F, Salmoiraghi, S, Cavagna, R, Buklijas, K, Elidi, L, Zanghi', P, Michelato, A, Delaini, F, Oldani, E, Intermesoli, T, Grassi, A, Gianfaldoni, G, Mannelli, F, Ferrero, D, Audisio, E, Terruzzi, E, De Paoli, L, Cattaneo, C, Borlenghi, E, Cavattoni, I, Tajana, M, Scattolin, A, Mattei, D, Corradini, P, Campiotti, L, Ciceri, F, Bernardi, M, Todisco, E, Cortelezzi, A, Falini, B, Pavoni, C, Bassan, R, Spinelli, O, Rambaldi, A, Caprioli, Chiara, Lussana, Federico, Salmoiraghi, Silvia, Cavagna, Roberta, Buklijas, Ksenija, Elidi, Lara, Zanghi', Pamela, Michelato, Anna, Delaini, Federica, Oldani, Elena, Intermesoli, Tamara, Grassi, Anna, Gianfaldoni, Giacomo, Mannelli, Francesco, Ferrero, Dario, Audisio, Ernesta, Terruzzi, Elisabetta, De Paoli, Lorella, Cattaneo, Chiara, Borlenghi, Erika, Cavattoni, Irene, Tajana, Monica, Scattolin, Anna Maria, Mattei, Daniele, Corradini, Paolo, Campiotti, Leonardo, Ciceri, Fabio, Bernardi, Massimo, Todisco, Elisabetta, Cortelezzi, Agostino, Falini, Brunangelo, Pavoni, Chiara, Bassan, Renato, Spinelli, Orietta, Rambaldi, Alessandro, Caprioli, C, Lussana, F, Salmoiraghi, S, Cavagna, R, Buklijas, K, Elidi, L, Zanghi', P, Michelato, A, Delaini, F, Oldani, E, Intermesoli, T, Grassi, A, Gianfaldoni, G, Mannelli, F, Ferrero, D, Audisio, E, Terruzzi, E, De Paoli, L, Cattaneo, C, Borlenghi, E, Cavattoni, I, Tajana, M, Scattolin, A, Mattei, D, Corradini, P, Campiotti, L, Ciceri, F, Bernardi, M, Todisco, E, Cortelezzi, A, Falini, B, Pavoni, C, Bassan, R, Spinelli, O, Rambaldi, A, Caprioli, Chiara, Lussana, Federico, Salmoiraghi, Silvia, Cavagna, Roberta, Buklijas, Ksenija, Elidi, Lara, Zanghi', Pamela, Michelato, Anna, Delaini, Federica, Oldani, Elena, Intermesoli, Tamara, Grassi, Anna, Gianfaldoni, Giacomo, Mannelli, Francesco, Ferrero, Dario, Audisio, Ernesta, Terruzzi, Elisabetta, De Paoli, Lorella, Cattaneo, Chiara, Borlenghi, Erika, Cavattoni, Irene, Tajana, Monica, Scattolin, Anna Maria, Mattei, Daniele, Corradini, Paolo, Campiotti, Leonardo, Ciceri, Fabio, Bernardi, Massimo, Todisco, Elisabetta, Cortelezzi, Agostino, Falini, Brunangelo, Pavoni, Chiara, Bassan, Renato, Spinelli, Orietta, and Rambaldi, Alessandro

Abstract

Secondary acute myeloid leukemia (sAML) after myelodysplastic or myeloproliferative disorders is a high-risk category currently identified by clinical history or specific morphological and cytogenetic abnormalities. However, in the absence of these features, uncertainties remain to identify the secondary nature of some cases otherwise defined as de novo AML. To test whether a chromatin-spliceosome (CS) mutational signature might better inform the definition of the de novo AML group, we analyzed a prospective cohort of 413 newly diagnosed AML patients enrolled into a randomized clinical trial (NILG AML 02/06) and provided with accurate cytogenetic and molecular characterization. Among clinically defined de novo AML, 17.6% carried CS mutations (CS-AML) and showed clinical characteristics closer to sAML (older age, lower white blood cell counts and higher rate of multilineage dysplasia). Outcomes in this group were adverse, more similar to those of sAML as compared to de novo AML (overall survival, 30% in CS-AML and 17% in sAML vs 61% in de novo AML, P<0.0001; disease free survival, 26% in CS-AML and 22% in sAML vs 54% of de novo AML, P<0.001) and independently confirmed by multivariable analysis. Allogeneic transplant in first complete remission improved survival in both sAML and CS-AML patients. In conclusion, these findings highlight the clinical significance of identifying CS-AML for improved prognostic prediction and potential therapeutic implications. (NILG AML 02/06: ClinicalTrials.gov Identifier: NCT00495287).

Published
2021

16. RISK-ADAPTED, MRD-DIRECTED THERAPY FOR YOUNG ADULTS WITH NEWLY DIAGNOSED ACUTE MYELOID LEUKEMIA: RESULTS OF THE AML1310 TRIAL OF THE GIMEMA GROUP

Author

Venditti, A, Piciocchi, A, Candoni, A, Melillo, L, Calafiore, V, Cairoli, R, De Fabritiis, P, Storti, G, Salutari, P, Lanza, F, Martinelli, G, Luppi, M, Mazza, P, Falini, B, Cuneo, A, Specchia, G, Fabbiano, F, Tafuri, A, Ronci, B, Tieghi, A, Fracchiolla, N, Capelli, D, Foa, R, Ronco, F, La Sala, E, Fazi, P, Maurillo, L, Buccisano, F, Del Principe, M, Lo Coco, F, Arcese, W, Amadori, S, Fracchiolla, NS, Del Principe, MI, Venditti, A, Piciocchi, A, Candoni, A, Melillo, L, Calafiore, V, Cairoli, R, De Fabritiis, P, Storti, G, Salutari, P, Lanza, F, Martinelli, G, Luppi, M, Mazza, P, Falini, B, Cuneo, A, Specchia, G, Fabbiano, F, Tafuri, A, Ronci, B, Tieghi, A, Fracchiolla, N, Capelli, D, Foa, R, Ronco, F, La Sala, E, Fazi, P, Maurillo, L, Buccisano, F, Del Principe, M, Lo Coco, F, Arcese, W, Amadori, S, Fracchiolla, NS, and Del Principe, MI

Published
2017

17. Simultaneous occurrence of acute myeloid leukaemia with mutated nucleophosmin (NPM1) in the same family

Author

Cazzaniga, G, Lo Nigro, L, Cifola, I, Milone, G, Schnittger, S, Haferlach, T, Mirabile, E, Costantino, F, Martelli, M, Mastrodicasa, E, Di Raimondo, F, Aversa, F, Biondi, A, Falini, B, Martelli, MP, Falini, B., BIONDI, ANDREA, Cazzaniga, G, Lo Nigro, L, Cifola, I, Milone, G, Schnittger, S, Haferlach, T, Mirabile, E, Costantino, F, Martelli, M, Mastrodicasa, E, Di Raimondo, F, Aversa, F, Biondi, A, Falini, B, Martelli, MP, Falini, B., and BIONDI, ANDREA

Published
2009

18. Quantitative assessment of minimal residual disease in acute myeloid leukemia carrying nucleophosmin (NPM1) gene mutations

Author

Gorello, P, Cazzaniga, G, Alberti, F, Dell'Oro, M, Gottardi, E, Specchia, G, Roti, G, Rosati, R, Martelli, M, Diverio, D, Lo Coco, F, Biondi, A, Saglio, G, Mecucci, C, Falini, B, Dell'Oro, MG, Martelli, MF, Falini, B., BIONDI, ANDREA, Gorello, P, Cazzaniga, G, Alberti, F, Dell'Oro, M, Gottardi, E, Specchia, G, Roti, G, Rosati, R, Martelli, M, Diverio, D, Lo Coco, F, Biondi, A, Saglio, G, Mecucci, C, Falini, B, Dell'Oro, MG, Martelli, MF, Falini, B., and BIONDI, ANDREA

Abstract

Mutations in exon 12 of the nucleophosmin (NPM1) gene occur in about 60% of adult AML with normal karyotype. By exploiting a specific feature of NPM1 mutants, that is insertion at residue 956 or deletion/insertion at residue 960, we developed highly sensitive, real-time quantitative (RQ) polymerase chain reaction (PCR) assays, either in DNA or RNA, that are specific for various NPM1 mutations. In all 13 AML patients carrying NPM1 mutations at diagnosis, cDNA RQ-PCR showed > 30000 copies of NPM1-mutated transcript. A small or no decrease in copies was observed in three patients showing partial or no response to induction therapy. The number of NPM1-mutated copies was markedly reduced in 10 patients achieving complete hematological remission (five cases:< 100 copies; five cases: 580-5046 copies). In four patients studied at different time intervals, the number of NPM1 copies closely correlated with clinical status and predicted impending hematological relapse in two. Thus, reliable, sensitive RQ-PCR assays for NPM1 mutations can now monitor and quantify MRD in AML patients with normal karyotype and NPM1 gene mutations.

Published
2006

19. Nucleophosmin mutations in childhood acute myelogenous leukemia with normal karyotype

Author

Cazzaniga, G, Dell'Oro, M, Mecucci, C, Giarin, E, Masetti, R, Rossi, V, Locatelli, F, Martelli, M, Basso, G, Pession, A, Biondi, A, Falini, B, Dell'Oro, MG, Martelli, MF, Falini, B., BIONDI, ANDREA, Cazzaniga, G, Dell'Oro, M, Mecucci, C, Giarin, E, Masetti, R, Rossi, V, Locatelli, F, Martelli, M, Basso, G, Pession, A, Biondi, A, Falini, B, Dell'Oro, MG, Martelli, MF, Falini, B., and BIONDI, ANDREA

Abstract

Nucleophosmin (NPM) is a nucleocytoplasmic shuttling protein involved in leukemia-associated chromosomal translocations, and it regulates the alternate reading frame (ARF)-p53 tumor-suppressor pathway. Recently, it has been demonstrated that mutations of the NPM1 gene alter the protein at its C-terminal, causing its cytoplasmic localization. Cytoplasmic NPM was detected in 35% of adult patients with primary non-French-American-British (FAB) classification M3 acute myeloid leukemia (AML), associated mainly with normal karyotype. We evaluated the prevalence of the NPM1 gene mutation in non-M3 childhood AML patients enrolled in the ongoing Associazione Italiana di Ematologia e Oncologia Pediatrica (AIEOP-AML02) protocol in Italy. NPM1 mutations were found in 7 (6.5%) of 107 successfully analyzed patients. NPM1-mutated patients carried a normal karyotype (7/26, 27.1%) and were older in age. Thus, the NPM1 mutation is a frequent abnormality in AML patients without known genetic marker; the mutation may represent a new target to monitor minimal residual disease in AML and a potential candidate for alternative and targeted treatments.

Published
2005

20. Immunohistochemical differentiation between follicular lymphoma and nodal marginal zone lymphoma - combined performance of multiple markers

Author

Brand, M. van den, Mathijssen, J.J., Garcia-Garcia, M., Hebeda, K.M., Groenen, P.J.T.A., Falini, B., Serrano, S., Krieken, J.H.J.M. van, Brand, M. van den, Mathijssen, J.J., Garcia-Garcia, M., Hebeda, K.M., Groenen, P.J.T.A., Falini, B., Serrano, S., and Krieken, J.H.J.M. van

Abstract

Contains fulltext : 153070.pdf (publisher's version ) (Open Access)

Published
2015

21. Immunohistochemical differentiation between follicular lymphoma and nodal marginal zone lymphoma - combined performance of multiple markers

Author

Brand, M. van den, Mathijssen, J.J., Garcia-Garcia, M., Hebeda, K.M., Groenen, P.J.T.A., Falini, B., Serrano, S., Krieken, J.H.J.M. van, Brand, M. van den, Mathijssen, J.J., Garcia-Garcia, M., Hebeda, K.M., Groenen, P.J.T.A., Falini, B., Serrano, S., and Krieken, J.H.J.M. van

Abstract

Contains fulltext : 153070.pdf (publisher's version ) (Open Access)

Published
2015

22. Differences among young adults, adults and elderly chronic myeloid leukemia patients

Author

Castagnetti, F, Gugliotta, G, Baccarani, M, Breccia, M, Specchia, G, Levato, L, Abruzzese, E, Rossi, G, Iurlo, A, Martino, B, Pregno, P, Stagno, F, Cuneo, A, Bonifacio, M, Gobbi, M, Russo, D, Gozzini, A, Tiribelli, M, De Vivo, A, Alimena, G, Cavo, M, Martinelli, G, Pane, F, Saglio, G, Rosti, G, Salvi, F, Pini, M, Leoni, P, Rupoli, S, Galieni, P, Bigazzi, C, Cantore, N, Palmieri, F, Albano, F, Russo Rossi, A, Rambaldi, A, Intermesoli, T, Palandri, F, Testoni, N, Luatti, S, Soverini, S, Iacobucci, I, Bochicchio, M, Apolinari, M, Fogli, M, Cervello, I, Capucci, A, Malagola, M, Malpignano, A, Girasoli, M, Angelucci, E, Usala, E, Storti, S, De Biasi, E, Tagariello, G, Sartori, R, Di Raimondo, F, Vigneri, P, Impera, S, Molica, S, Lanza, F, Viganò, C, Grasso, M, Rapezzi, D, Cavazzini, F, Bosi, A, Santini, V, Capalbo, S, Spinosa, G, Pierri, I, Bergamaschi, M, Carella, A, Bacigalupo, A, De Blasio, A, Ciccone, F, Di Renzo, N, Musolino, C, Russo, S, Cortelezzi, A, Morra, E, Pungolino, E, Luppi, M, Marasca, R, Pogliani, E, GAMBACORTI PASSERINI, C, Luciano, L, Ferrara, F, Annunziata, M, Latte, G, Noli, D, Rege Cambrin, G, Fava, C, Semenzato, G, Binotto, G, Fabbiano, F, Turri, D, Siragusa, S, Caracciolo, C, Musso, M, Porretto, F, Aversa, F, Crugnola, M, Cazzola, M, Orlandi, E, Falini, B, Falzetti, F, Visani, G, Isidori, A, Fioritoni, G, Di Lorenzo, R, Vallisa, D, Trabacchi, E, Petrini, M, Galimberti, S, Pizzuti, M, Zaccaria, A, Salvucci, M, Ronco, F, Ielo, D, Merli, F, Avanzini, P, Tosi, P, Merli, A, Musto, P, De Stefano, V, Sica, S, Latagliata, R, De Fabritiis, P, Trawiska, M, Majolino, I, Pacilli, L, Ronci, B, Cedrone, M, Petti, M, Pisani, F, Tafuri, A, Montefusco, E, Iuliano, F, Dore, F, Pardini, S, Bocchia, M, Defina, M, Liberati, A, Luzzi, D, Boccadoro, M, Ferrero, D, Vitolo, U, Gherlinzoni, F, Calistri, E, Fanin, R, Pizzolo, G, Meneghini, V, Rodighiero, F, D'Emilio, A, GAMBACORTI PASSERINI, CARLO, D'Emilio, A., Castagnetti, F, Gugliotta, G, Baccarani, M, Breccia, M, Specchia, G, Levato, L, Abruzzese, E, Rossi, G, Iurlo, A, Martino, B, Pregno, P, Stagno, F, Cuneo, A, Bonifacio, M, Gobbi, M, Russo, D, Gozzini, A, Tiribelli, M, De Vivo, A, Alimena, G, Cavo, M, Martinelli, G, Pane, F, Saglio, G, Rosti, G, Salvi, F, Pini, M, Leoni, P, Rupoli, S, Galieni, P, Bigazzi, C, Cantore, N, Palmieri, F, Albano, F, Russo Rossi, A, Rambaldi, A, Intermesoli, T, Palandri, F, Testoni, N, Luatti, S, Soverini, S, Iacobucci, I, Bochicchio, M, Apolinari, M, Fogli, M, Cervello, I, Capucci, A, Malagola, M, Malpignano, A, Girasoli, M, Angelucci, E, Usala, E, Storti, S, De Biasi, E, Tagariello, G, Sartori, R, Di Raimondo, F, Vigneri, P, Impera, S, Molica, S, Lanza, F, Viganò, C, Grasso, M, Rapezzi, D, Cavazzini, F, Bosi, A, Santini, V, Capalbo, S, Spinosa, G, Pierri, I, Bergamaschi, M, Carella, A, Bacigalupo, A, De Blasio, A, Ciccone, F, Di Renzo, N, Musolino, C, Russo, S, Cortelezzi, A, Morra, E, Pungolino, E, Luppi, M, Marasca, R, Pogliani, E, GAMBACORTI PASSERINI, C, Luciano, L, Ferrara, F, Annunziata, M, Latte, G, Noli, D, Rege Cambrin, G, Fava, C, Semenzato, G, Binotto, G, Fabbiano, F, Turri, D, Siragusa, S, Caracciolo, C, Musso, M, Porretto, F, Aversa, F, Crugnola, M, Cazzola, M, Orlandi, E, Falini, B, Falzetti, F, Visani, G, Isidori, A, Fioritoni, G, Di Lorenzo, R, Vallisa, D, Trabacchi, E, Petrini, M, Galimberti, S, Pizzuti, M, Zaccaria, A, Salvucci, M, Ronco, F, Ielo, D, Merli, F, Avanzini, P, Tosi, P, Merli, A, Musto, P, De Stefano, V, Sica, S, Latagliata, R, De Fabritiis, P, Trawiska, M, Majolino, I, Pacilli, L, Ronci, B, Cedrone, M, Petti, M, Pisani, F, Tafuri, A, Montefusco, E, Iuliano, F, Dore, F, Pardini, S, Bocchia, M, Defina, M, Liberati, A, Luzzi, D, Boccadoro, M, Ferrero, D, Vitolo, U, Gherlinzoni, F, Calistri, E, Fanin, R, Pizzolo, G, Meneghini, V, Rodighiero, F, D'Emilio, A, GAMBACORTI PASSERINI, CARLO, and D'Emilio, A.

Abstract

Background: The incidence of chronic myeloid leukemia (CML) increases with age, but it is unclear how the characteristics of the disease vary with age. In children, where CML is very rare, it presents with more aggressive features, including huge splenomegaly, higher cell count and higher blast cell percentage. Patients and methods: To investigate if after childhood the disease maintains or loses these characteristics of aggressiveness, we analyzed 2784 adult patients, at least 18 years old, registered by GIMEMA CMLWP over a 40-year period. Results: Young adults (YAs: 18-29 years old) significantly differed from adults (30-59 years old) and elderly patients (at least 60 years old) particularly for the frequency of splenomegaly (71%, 63% and 55%, P < 0.001), and the greater spleen size (median value: 4.5, 3.0 and 1.0 cm, P < 0.001). According to the EUTOS score, that is age-independent, high-risk patients were more frequent among YAs, than among adult and elderly patients (18%, 9% and 6%, P < 0.001). In tyrosine kinase inhibitors-treated patients, the rates of complete cytogenetic and major molecular response were lower in YAs, and the probability of transformation was higher (16%, 5% and 7%, P = 0.011). Conclusions: The characteristics of CML or the host response to leukemia differ with age. The knowledge of these differences and of their causes may help to refine the treatment and to improve the outcome.

Published
2015

23. Nucleophosmin mutations alter its nucleolar localization by impairing G-quadruplex binding at ribosomal DNA

Author

Chiarella, S, De Cola, A, Scaglione, Giovanni Luca, Carletti, E, Graziano, V, Barcaroli, D, Lo Sterzo, C, Di Matteo, A, Di Ilio, C, Falini, B, Arcovito, Alessandro, De Laurenzi, V, Federici, L., Arcovito, Alessandro (ORCID:0000-0002-8384-4844), Chiarella, S, De Cola, A, Scaglione, Giovanni Luca, Carletti, E, Graziano, V, Barcaroli, D, Lo Sterzo, C, Di Matteo, A, Di Ilio, C, Falini, B, Arcovito, Alessandro, De Laurenzi, V, Federici, L., and Arcovito, Alessandro (ORCID:0000-0002-8384-4844)

Abstract

Nucleophosmin (NPM1) is an abundant nucleolar protein implicated in ribosome maturation and export, centrosome duplication and response to stress stimuli. NPM1 is the most frequently mutated gene in acute myeloid leukemia. Mutations at the C-terminal domain led to variant proteins that aberrantly and stably translocate to the cytoplasm. We have previously shown that NPM1 C-terminal domain binds with high affinity G-quadruplex DNA. Here, we investigate the structural determinants of NPM1 nucleolar localization. We show that NPM1 interacts with several G-quadruplex regions found in ribosomal DNA, both in vitro and in vivo. Furthermore, the most common leukemic NPM1 variant completely loses this activity. This is the consequence of G-quadruplex-binding domain destabilization, as mutations aimed at refolding the leukemic variant also result in rescuing the G-quadruplex-binding activity and nucleolar localization. Finally, we show that treatment of cells with a G-quadruplex selective ligand results in wild-type NPM1 dislocation from nucleoli into nucleoplasm. In conclusion, this work establishes a direct correlation between NPM1 G-quadruplex binding at rDNA and its nucleolar localization, which is impaired in the acute myeloid leukemia-associated protein variants.

Published
2013

24. Low prevalence of IDH1 gene mutation in childhood AML in Italy

Author

Piazzi, M, Ferrari, G, Masetti, R, Falini, B, Martinelli, F, Basso, G, Biondi, A, Pession, A, Cazzaniga, G, Cazzaniga, G., BIONDI, ANDREA, Piazzi, M, Ferrari, G, Masetti, R, Falini, B, Martinelli, F, Basso, G, Biondi, A, Pession, A, Cazzaniga, G, Cazzaniga, G., and BIONDI, ANDREA

Published
2011

25. Gene expression profiling of isolated tumour cells from anaplastic large cell lymphomas : insights into its cellular origin, pathogenesis and relation to Hodgkin lymphoma

Author

Eckerle, S., Brune, V., Döring, C., Tiacci, E., Bohle, V., Sundström, Christer, Kodet, R., Paulli, M., Falini, B., Klapper, W., Chaubert, A. B., Willenbrock, K., Metzler, D., Bräuninger, A., Küppers, Ralf, Hansmann, M-L., Eckerle, S., Brune, V., Döring, C., Tiacci, E., Bohle, V., Sundström, Christer, Kodet, R., Paulli, M., Falini, B., Klapper, W., Chaubert, A. B., Willenbrock, K., Metzler, D., Bräuninger, A., Küppers, Ralf, and Hansmann, M-L.

Abstract

Anaplastic large cell lymphoma (ALCL) is a main type of T-cell lymphomas and comprises three distinct entities: systemic anaplastic lymphoma kinase (ALK) positive, systemic ALK(-) and cutaneous ALK(-) ALCL (cALCL). Little is known about their pathogenesis and their cellular origin, and morphological and immunophenotypical overlap exists between ALK(-) ALCL and classical Hodgkin lymphoma (cHL). We conducted gene expression profiling of microdissected lymphoma cells of five ALK(+) and four ALK(-) systemic ALCL, seven cALCL and sixteen cHL, and of eight subsets of normal T and NK cells. The analysis supports a derivation of ALCL from activated T cells, but the lymphoma cells acquired a gene expression pattern hampering an assignment to a CD4(+), CD8(+) or CD30(+) T-cell origin. Indeed, ALCL display a down-modulation of many T-cell characteristic molecules. All ALCL types show significant expression of NFkappaB target genes and upregulation of genes involved in oncogenesis (e.g. EZH2). Surprisingly, few genes are differentially expressed between systemic and cALCL despite their different clinical behaviour, and between ALK(-) ALCL and cHL despite their different cellular origin. ALK(+) ALCL are characterized by expression of genes regulated by pathways constitutively activated by ALK. This study provides multiple novel insights into the molecular biology and pathogenesis of ALCL.

Published
2009
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26. Nucleophosmin leukaemic mutants contain C-terminus peptides that bind HLA class I molecules

Author

UCL - MD/MIGE - Département de microbiologie, d'immunologie et de génétique, Liso, A., Colau, Didier, Benmaamar, R., De Groot, A., Martin, W., Benedetti, R., Specchia, G., Martelli, M. P., Coulie, Pierre, Falini, B., UCL - MD/MIGE - Département de microbiologie, d'immunologie et de génétique, Liso, A., Colau, Didier, Benmaamar, R., De Groot, A., Martin, W., Benedetti, R., Specchia, G., Martelli, M. P., Coulie, Pierre, and Falini, B.

Published
2008

27. A one-mutation mathematical model can explain the age incidence of acute myeloid leukemia with mutated nucleophosmin (NPM1)

Author

Liso, A. (Arcangelo), Castiglione, F. (Filippo), Cappuccio, A. (Antonio), Stracci, F. (Fabrizio), Schlenk, R.F. (Richard), Amadori, S. (Sergio), Thiede, C. (Christian), Schnittger, S. (Susanne), Valk, P.J.M. (Peter), Döhner, K. (Konstanze), Martelli, M.F. (Massimo F.), Schaich, M. (Markus), Krauter, J., Ganser, A. (Arnold), Bolli, N. (Niccolò), Löwenberg, B. (Bob), Haferlach, T. (Torsten), Ehninger, G. (Gerhard), Mandelli, F. (Franco), Michor, F. (Franziska), Falini, B., Liso, A. (Arcangelo), Castiglione, F. (Filippo), Cappuccio, A. (Antonio), Stracci, F. (Fabrizio), Schlenk, R.F. (Richard), Amadori, S. (Sergio), Thiede, C. (Christian), Schnittger, S. (Susanne), Valk, P.J.M. (Peter), Döhner, K. (Konstanze), Martelli, M.F. (Massimo F.), Schaich, M. (Markus), Krauter, J., Ganser, A. (Arnold), Bolli, N. (Niccolò), Löwenberg, B. (Bob), Haferlach, T. (Torsten), Ehninger, G. (Gerhard), Mandelli, F. (Franco), Michor, F. (Franziska), and Falini, B.

Abstract

Acute myeloid leukemia with mutated NPM1 gene and aberrant cytoplasmic expression of nucleophosmin (NPMc+acute myeloid leukemia) shows distinctive biological and clinical features. Experimental evidence of the oncogenic potential of the nucleophosmin mutant is, however, still lacking, and it is unclear whether other genetic lesion(s), e.g. FLT3 internal tandem duplication, cooperate with NPM1 mutations in acute myeloid leukemia development. An analysis of age-specific incidence, together with mathematical modeling of acute myeloid leukemia epidemiology, can help to uncover the number of genetic events needed to cause leukemia. We collected data on age at diagnosis of acute myeloid leukemia patients from five European Centers in Germany, The Netherlands and Italy, and determined the age-specific incidence of AML with mutated NPM1 (a total of 1,444 cases) for each country. Linear regression of the curves representing age-specific rates of diagnosis per year showed similar slopes of about 4 on a double logarithmic scale. We then adapted a previously designed mathematical model of hematopoietic tumorigenesis to analyze the age incidence of acute myeloid leukemia with mutated NPM1 and found that a one-mutation model can explain the incidence curve of this leukemia entity. This model fits with the hypothesis that NPMc+acute myeloid leukemia arises from an NPM1 mutation with haploinsufficiency of the wild-type NPM1 allele.

Published
2008
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28. A one-mutation mathematical model can explain the age incidence of acute myeloid leukemia with mutated nucleophosmin (NPM1)

Author

Liso, A, Castiglione, F, Cappuccio, A, Stracci, F, Schlenk, RF, Amadori, S, Thiede, C, Schnittger, S, Valk, Peter, Dohner, K, Martelli, MF, Schaich, M, Krauter, J, Ganser, A, Martelli, MP, Bolli, N, Löwenberg, Bob, Haferlach, T, Ehninger, G, Mandelli, F, Dohner, H, Michor, F, Falini, B, Liso, A, Castiglione, F, Cappuccio, A, Stracci, F, Schlenk, RF, Amadori, S, Thiede, C, Schnittger, S, Valk, Peter, Dohner, K, Martelli, MF, Schaich, M, Krauter, J, Ganser, A, Martelli, MP, Bolli, N, Löwenberg, Bob, Haferlach, T, Ehninger, G, Mandelli, F, Dohner, H, Michor, F, and Falini, B

Abstract

Acute myeloid leukemia with mutated NPM1 gene and aberrant cytoplasmic expression of nucleophosmin (NPMc(+) acute myeloid leukemia) shows distinctive biological and clinical features. Experimental evidence of the oncogenic potential of the nucleophosmin mutant is, however, still lacking, and it is unclear whether other genetic lesion(s), e.g. FLT3 internal tandem duplication, cooperate with NPM1 mutations in acute myeloid leukemia development. An analysis of age-specific incidence, together with mathematical modeling of acute myeloid leukemia epidemiology, can help to uncover the number of genetic events needed to cause leukemia. We collected data on age at diagnosis of acute myeloid leukemia patients from five European Centers in Germany, The Netherlands and Italy, and determined the age-specific incidence of AML with mutated NPM1 (a total of 1,444 cases) for each country. Linear regression of the curves representing age-specific rates of diagnosis per year showed similar slopes of about 4 on a double logarithmic scale. We then adapted a previously designed mathematical model of hematopoietic tumorigenesis to analyze the age incidence of acute myeloid leukemia with mutated NPM1 and found that a one-mutation model can explain the incidence curve of this leukemia entity. This model fits with the hypothesis that NPMc(+) acute myeloid leukemia arises from an NPM1 mutation with haploinsufficiency of the wild-type NPM1 allele.

Published
2008

29. Both carboxy-terminus NES motif and mutated tryptophan(s) are crucial for aberrant nuclear export of nucleophosmin leukemic mutants in NPMc+ AML

Author

Falini, B, Bolli, N, Shan, J, Martelli, M, Liso, A, Pucciarini, A, Bigerna, B, Pasqualucci, L, Mannucci, R, Rosati, R, Gorello, P, Diverio, D, Roti, G, Tiacci, E, Cazzaniga, G, Biondi, A, Schnittger, S, Haferlach, T, Hiddemann, W, Gu, W, Mecucci, C, Nicoletti, I, Martelli, MP, Martelli, MF, Nicoletti, I., BIONDI, ANDREA, Falini, B, Bolli, N, Shan, J, Martelli, M, Liso, A, Pucciarini, A, Bigerna, B, Pasqualucci, L, Mannucci, R, Rosati, R, Gorello, P, Diverio, D, Roti, G, Tiacci, E, Cazzaniga, G, Biondi, A, Schnittger, S, Haferlach, T, Hiddemann, W, Gu, W, Mecucci, C, Nicoletti, I, Martelli, MP, Martelli, MF, Nicoletti, I., and BIONDI, ANDREA

Abstract

We recently identified aberrant cytoplasmic expression of nucleophosmin (NPM) as the immunohistochemical marker of a large subgroup of acute myeloid leukemia (AML) (about one-third of adult AML) that is characterized by normal karyotype and mutations occurring at the exon-12 of the NPM gene. In this paper, we have elucidated the molecular mechanism underlying the abnormal cytoplasmic localization of NPM. All 29 AML-associated mutated NPM alleles so far identified encode abnormal proteins which have acquired at the C-terminus a nuclear export signal (NES) motif and lost both tryptophan residues 288 and 290 (or only the residue 290) which determine nucleolar localization. We show for the first time that both alterations are crucial for NPM mutant export from nucleus to cytoplasm. In fact, the cytoplasmic accumulation of NPM is blocked by leptomycin-B and ratjadones, specific exportin-1/Crm1-inhibitors, and by reinsertion of tryptophan residues 288 and 290, which respectively relocate NPM mutants in the nucleoplasm and nucleoli. NPM leukemic mutants in turn recruit the wild-type NPM from nucleoli to nucleoplasm and cytoplasm. These findings indicate that potential therapeutic strategies aimed to retarget NPM to its physiological sites will have to overcome 2 obstacles, the new NES motif and the mutated tryptophan(s) at the NPM mutant C-terminus.

Published
2006

30. Sch proteins are localized on endoplasmic reticulum membranes and are redistributed after tyrosine kinase receptor activation.

Author

Lotti, L V, Lanfrancone, L, Migliaccio, E, Zompetta, C, Pelicci, G, Salcini, A E, Falini, B, Pelicci, P G, Torrisi, M R, Lotti, L V, Lanfrancone, L, Migliaccio, E, Zompetta, C, Pelicci, G, Salcini, A E, Falini, B, Pelicci, P G, and Torrisi, M R

Abstract

Udgivelsesdato: 1996-May, The intracellular localization of Shc proteins was analyzed by immunofluorescence and immunoelectron microscopy in normal cells and cells expressing the epidermal growth factor receptor or the EGFR/erbB2 chimera. In unstimulated cells, the immunolabeling was localized in the central perinuclear area of the cell and mostly associated with the cytosolic side of rough endoplasmic reticulum membranes. Upon epidermal growth factor treatment and receptor tyrosine kinase activation, the immunolabeling became peripheral and was found to be associated with the cytosolic surface of the plasma membrane and endocytic structures, such as coated pits and endosomes, and with the peripheral cytosol. Receptor activation in cells expressing phosphorylation-defective mutants of Shc and erbB-2 kinase showed that receptor autophosphorylation, but not Shc phosphorylation, is required for redistribution of Shc proteins. The rough endoplasmic reticulum localization of Shc proteins in unstimulated cells and their massive recruitment to the plasma membrane, endocytic structures, and peripheral cytosol following receptor tyrosine kinase activation could account for multiple putative functions of the adaptor protein.

Published
1996

31. Sch proteins are localized on endoplasmic reticulum membranes and are redistributed after tyrosine kinase receptor activation.

Author

Lotti, L V, Lanfrancone, L, Migliaccio, E, Zompetta, C, Pelicci, G, Salcini, A E, Falini, B, Pelicci, P G, Torrisi, M R, Lotti, L V, Lanfrancone, L, Migliaccio, E, Zompetta, C, Pelicci, G, Salcini, A E, Falini, B, Pelicci, P G, and Torrisi, M R

Abstract

Udgivelsesdato: 1996-May, The intracellular localization of Shc proteins was analyzed by immunofluorescence and immunoelectron microscopy in normal cells and cells expressing the epidermal growth factor receptor or the EGFR/erbB2 chimera. In unstimulated cells, the immunolabeling was localized in the central perinuclear area of the cell and mostly associated with the cytosolic side of rough endoplasmic reticulum membranes. Upon epidermal growth factor treatment and receptor tyrosine kinase activation, the immunolabeling became peripheral and was found to be associated with the cytosolic surface of the plasma membrane and endocytic structures, such as coated pits and endosomes, and with the peripheral cytosol. Receptor activation in cells expressing phosphorylation-defective mutants of Shc and erbB-2 kinase showed that receptor autophosphorylation, but not Shc phosphorylation, is required for redistribution of Shc proteins. The rough endoplasmic reticulum localization of Shc proteins in unstimulated cells and their massive recruitment to the plasma membrane, endocytic structures, and peripheral cytosol following receptor tyrosine kinase activation could account for multiple putative functions of the adaptor protein.

Published
1996

32. Lymphoma Classification Proposal - Clarification

Author

UCL, Harris, NL., Jaffe, ES., Stein, H., Banks, PM., Chan, JKC., Cleary, ML., Delsol, G., Dewolfpeeters, C., Falini, B., Gatter, KC., Grogan, TM., Isaacson, PG., Knowles, DM., Mason, DY., Mullerhermelink, HK., Pileri, SA., Piris, MA., Ralfkiaer, E., Warnke, RA., UCL, Harris, NL., Jaffe, ES., Stein, H., Banks, PM., Chan, JKC., Cleary, ML., Delsol, G., Dewolfpeeters, C., Falini, B., Gatter, KC., Grogan, TM., Isaacson, PG., Knowles, DM., Mason, DY., Mullerhermelink, HK., Pileri, SA., Piris, MA., Ralfkiaer, E., and Warnke, RA.

Published
1995

33. A Revised European-american Classification of Lymphoid Neoplasms Proposed By the International Lymphoma Study-group - a Summary Version

Author

UCL, Chan, JKC., Banks, PM., Cleary, ML., Delsol, G., Dewolfpeeters, C., Falini, B., Gatter, KC., Grogan, TM., Harris, NL., Isaacson, PG., Jaffe, ES., Knowles, DM., Mason, DY., Mullerhermelink, HK., Pileri, SA., Piris, MA., Ralfkiaer, E., Stein, H., Warnke, RA., UCL, Chan, JKC., Banks, PM., Cleary, ML., Delsol, G., Dewolfpeeters, C., Falini, B., Gatter, KC., Grogan, TM., Harris, NL., Isaacson, PG., Jaffe, ES., Knowles, DM., Mason, DY., Mullerhermelink, HK., Pileri, SA., Piris, MA., Ralfkiaer, E., Stein, H., and Warnke, RA.

Published
1995

34. A Revised European-american Classification of Lymphoid Neoplasms - a Proposal From the International Lymphoma Study-group

Author

UCL, Harris, NL., Jaffe, ES., Stein, H., Banks, PM., Chan, JKC., Cleary, ML., Delsol, G., Dewolfpeeters, C., Falini, B., Gatter, KC., Grogan, TM., Isaacson, PG., Knowles, DM., Mason, DY., Mullerhermelink, HK., Pileri, SA., Piris, MA., Ralfkiaer, E., Warnke, RA., UCL, Harris, NL., Jaffe, ES., Stein, H., Banks, PM., Chan, JKC., Cleary, ML., Delsol, G., Dewolfpeeters, C., Falini, B., Gatter, KC., Grogan, TM., Isaacson, PG., Knowles, DM., Mason, DY., Mullerhermelink, HK., Pileri, SA., Piris, MA., Ralfkiaer, E., and Warnke, RA.

Published
1994

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